Pharmacological effects on anaplerotic pathways alter the metabolic landscape in the tumor microenvironment, causing unpredictable, sustained anti-tumor immunity

To achieve sustained anti-tumor immunity, tumor-infiltrating effector CD8 T lymphocytes (CD8 TILs) must be able to produce cytokines, including IFN gamma, and proliferate robustly within the local tumor tissue upon antigen recognition. IFN gamma production by CD8 TILs depends on glycolysis, whereas their proliferation additionally requires oxidative phosphorylation (OxPhos). The level of OxPhos, and hence the oxygen consumption rate, depends on mitochondrial biogenesis and requires the loading of metabolic precursors into the tricarboxylic acid cycle to keep it functioning. This is referred to as anaplerosis. Recent advances in the field of immuno-metabolism have shown the impact of pharmacological agents on anaplerotic pathways, resulting in metabolic down-regulation in tumor cells; in contrast, the agents trigger sustained anti-tumor immunity by up-regulating both glycolysis and OxPhos in CD8 TILs. The opposing effects of pharmacological inhibition (and/or activation) on anaplerosis in tumor cells and CD8 TILs are unpredictable. Careful dissection of the underlying mechanism might confer important knowledge, helping us to step into a new era for cancer immunotherapy.